Airway remodeling is the term applied to the structural changes observed in the airway in asthma. Although current NIH guidelines recommend maintaining a goal of normal lung function in asthma, current therapeutic strategies do not specifically target airway remodeling as the cellular and molecular mechanisms that result in remodeling are not well defined and thus therapeutic targets are not well understood. Thus, there is an important need to identify mechanisms by which airway remodeling is mediated so that potential novel therapies could be directed at these pathways. In addition, characterization of these pathways could lead to the development of non-invasive blood or sputum biomarkers to identify, monitor, and perhaps subset, patients with asthma and remodeled airways. This UCSD AADCRC proposal will be directed by David Broide (Professor of Medicine) and include three projects (Broide, Croft, Zuraw) that will investigate mechanisms of airway remodeling in asthmatics exposed to allergen and rhinovirus common triggers of asthma. Thus, the overall hypothesis that will be explored in all three projects is that exposure to allergen triggers expression of inflammatory and remodeling pathways in allergic asthmatics that are exacerbated by exposure to respiratory viruses such as rhinovirus. The specific hypothesis that will be explored in each project and that will be driven by samples from asthmatics, is that the innate immune response (airway epithelium, macrophages, natural helper cells) play an important role in initiating and perpetuating the inflammatory and airway remodeling response to environmental triggers in allergic asthmatics. The three interrelated projects will focus on Innate inflammation and airway remodeling (Broide, Project 1), TNF-R family members, inflammation and remodeling (Croft, Project 2), and Epithelial GILZ inflammation and remodeling (Zuraw, Project 3) and be supported by Administrative Core A, and Asthma Clinical Core B which will be a source of sputum, BAL, endobronchial biopsy, and blood samples from asthma and control subjects provided by investigators in Core B (Ramsdell, Harrell, and Thistlethwaite, UCSD; Proud and Leigh, University of Calgary; and Hamid, McGill University). An lOFM Core is also proposed as requested by the RFA.